scholarly journals Molecular mechanisms of enzyme dysfunction in human phosphoglucomutase-1 deficiency

2019 ◽  
Author(s):  
◽  
Kyle Matthew Stiers
Keyword(s):  
Molecular Mechanisms ◽  
Structural Features ◽  
Therapeutic Interventions ◽  
Structural Studies ◽  
X Ray ◽  
Missense Variants ◽  
X Ray Crystallography ◽  
Ancient Lineage ◽  
Research Opportunity

Human phosphoglucomutase-1 (PGM1) belongs to the [alpha]-D-phosphohexomutase superfamily, an ancient lineage of enzymes critical for carbohydrate metabolism. PGM1 catalyzes the interconversion of glucose-1-phosphate and glucose-6-phosphate, acting as the pivot between energy storage and utilization. Recently, PGM1 has been implicated as the monogenic cause of an inherited metabolic disease in humans, called PGM1 deficiency. The disease presents with highly variable phenotype in patients and is difficult to diagnose. Furthermore, genotype-phenotype relationships remain unclear-even in siblings with the same missense variants, no obvious correlation exists. PGM1 deficiency is a unique research opportunity due to the lack of clear rationale for varying effects of missense variants, availability of patient data, favorable in vitro behavior of recombinantly expressed PGM1, and the limited number of structural studies characterizing individual missense variants. In this work we have characterized multiple molecular mechanisms of disease through X-ray crystallography and biochemistry. Thus, this work provides a foundation for physicians to make much more accurate prognostic decisions when advising patients, identifies variants with possible therapeutic interventions, and informs us of key dynamics and structural features required for proper functioning of human PGM1.

Two new zinc(II) and mercury(II) complexes based on N,N′-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide): synthesis, crystal structures and antibacterial activities

2020 ◽  
Vol 76 (5) ◽  
pp. 476-482
Author(s):  
Al-Ameen Bariz OmarAli ◽  
Ahmed Jasim M. Al-Karawi ◽  
Adil A. Awad ◽  
Necmi Dege ◽  
Sevgi Kansız ◽  
...  
Keyword(s):  
Organic Ligand ◽  
Antibacterial Activities ◽  
Structural Features ◽  
Bacterial Strains ◽  
Tetrahedral Geometry ◽  
X Ray ◽  
X Ray Crystallography ◽  
Growth Inhibitory ◽  
The Difference

Reaction of N,N′-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide), C20H18F2N4O2, (LF ), with zinc chloride and mercury(II) chloride produced different types and shapes of neutral coordination complexes, namely, dichlorido[N,N′-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide)-κ2 N,O]zinc(II), [ZnCl2(C20H18F2N4O2)], (1), and dichlorido[N,N′-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide)-κ4 O,N,N′,O′]mercury(II), [HgCl2(C20H18F2N4O2)], (2). The organic ligand and its metal complexes are characterized using various techniques: IR, UV–Vis and nuclear magnetic resonance (NMR) spectroscopies, in addition to powder X-ray diffraction (PXRD), single-crystal X-ray crystallography and microelemental analysis. Depending upon the data from these analyses and measurements, a typical tetrahedral geometry was confirmed for zinc complex (1), in which the ZnII atom is located outside the bis(benzhydrazone) core. The HgII atom in (2) is found within the core and has a common octahedral structure. The in vitro antibacterial activities of the prepared compounds were evaluated against two different bacterial strains, i.e. gram positive Bacillus subtilis and gram negative Pseudomonas aeruginosa bacteria. The prepared compounds exhibited differentiated growth-inhibitory activities against these two bacterial strains based on the difference in their lipophilic nature and structural features.

scholarly journals Four-dimensional NOE-NOE spectroscopy of SARS-CoV-2 Main Protease to facilitate resonance assignment and structural analysis

2021 ◽  
Author(s):  
Angus J. Robertson ◽  
Jinfa Ying ◽  
Ad Bax
Keyword(s):  
Resonance Assignment ◽  
Structural Information ◽  
Structural Features ◽  
Structural Studies ◽  
Dipolar Relaxation ◽  
X Ray ◽  
X Ray Crystallography ◽  
Main Protease ◽  
4D Noesy ◽  
Exchange Broadening

Abstract. Resonance assignment and structural studies of larger proteins by NMR can be challenging when exchange broadening, multiple stable conformations, and back-exchanging the fully deuterated chain pose problems. These difficulties arise for the SARS-CoV-2 Main Protease, a homodimer of 2×306 residues. We demonstrate that the combination of four-dimensional (4D) TROSY-NOESY-TROSY spectroscopy and 4D NOESY-NOESY-TROSY spectroscopy provides an effective tool for delineating the 1H-1H dipolar relaxation network. In combination with detailed structural information obtained from prior X-ray crystallography work, such data are particularly useful for extending and validating resonances assignments, as well as for probing structural features.

scholarly journals o-Carboranylalkoxy-1,3,5-Triazine Derivatives: Synthesis, Characterization, X-ray Structural Studies, and Biological Activity

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2194 ◽  
Author(s):  
Guo Jin ◽  
Hyun Ban ◽  
Hiroyuki Nakamura ◽  
Jong-Dae Lee
Keyword(s):  
Biological Activity ◽  
B16 Melanoma ◽  
Molecular Structures ◽  
In Vitro Studies ◽  
Structural Studies ◽  
Triazine Ring ◽  
X Ray ◽  
X Ray Crystallography ◽  
Triazine Derivatives

Morpholine- and bis(2-methoxyethyl)amine-substituted 1,3,5-triazine derivatives containing an alkoxy-o-carborane in the 6-position of the triazine ring were successfully synthesized. The molecular structures of the methoxy- and ethoxy-o-carboranyl-1,3,5-triazines were established by X-ray crystallography. In vitro studies showed that the methylene bridged morpholine- and bis(2-methoxyethyl)amine-substituted o-carboranyl-1,3,5-triazines accumulated to high levels in B16 melanoma cells and exhibited higher cytotoxicity than p-boronophenylalanine.

Synthesis, Characterisation and Structural Studies of [Zn(phen)3][Fe(CN)5(NO)]·2H2O·0.25MeOH and [(bipy)2(H2O)Zn(μ-NC)Fe(CN)4(NO)]·0.5H2O

2003 ◽  
Vol 58 (9) ◽  
pp. 916-921 ◽  
Author(s):  
Amitabha Datta ◽  
Samiran Mitra ◽  
Georgina Rosair
Keyword(s):  
Infrared Spectroscopy ◽  
Thermogravimetric Analysis ◽  
Octahedral Geometry ◽  
Distorted Octahedral Geometry ◽  
Structural Studies ◽  
Crystal Lattices ◽  
X Ray ◽  
X Ray Crystallography ◽  
Distorted Octahedral ◽  
Solvent Molecules

Two new bimetallic complexes [Zn(phen)3][Fe(CN)5(NO)] · 2 H2O · 0.25 MeOH, (1) and [(bipy)2(H2O)Zn(μ-NC)Fe(CN)4(NO)] · 0.5 H2O, (2), have been isolated (where phen = 1,10-phenanthroline and bipy = bipyridyl) and characterised by X-ray crystallography [as the 2 H2O · 0.25 CH3OH solvate for (1) and hemihydrate for (2)] infrared spectroscopy and thermogravimetric analysis. Substitution of phenanthroline for bipyridyl resulted in a cyano-bridged bimetallic species rather than two discrete mononuclear metal complexes. The bond angles of Fe-N-O were shown to be practically linear for both 1 [179.2(7)°] and 2 [178.3(3)°], and the Zn atoms have distorted octahedral geometry. The solvent molecules in both crystal lattices take part in forming hydrogen-bonded networks.

A novel palladium (II) complex with a ferrocene-based ligand: Synthesis, X-ray crystallography and in vitro anticancer activity study

2021 ◽  
Vol 126 ◽  
pp. 108448
Author(s):  
Guoyuan Du ◽  
Zhonghui Zhang ◽  
Xiangyu Lu ◽  
Wentao Cai ◽  
Liji Wu ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
X Ray ◽  
X Ray Crystallography ◽  
Ligand Synthesis

scholarly journals Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

2014 ◽  
Vol 58 (10) ◽  
pp. 6044-6055 ◽  
Author(s):  
Tanira M. Bastos ◽  
Marília I. F. Barbosa ◽  
Monize M. da Silva ◽  
José W. da C. Júnior ◽  
Cássio S. Meira ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Inhibitory Concentration ◽  
Content Type ◽  
X Ray ◽  
X Ray Crystallography ◽  
Ruthenium Nitrosyl ◽  
Index Analysis ◽  
Antiparasitic Drug ◽  
Drug Complex

ABSTRACTcis-[RuCl(NO2)(dppb)(5,5′-mebipy)] (complex 1),cis-[Ru(NO2)2(dppb)(5,5′-mebipy)] (complex 2),ct-[RuCl(NO)(dppb)(5,5′-mebipy)](PF6)2(complex 3), andcc-[RuCl(NO)(dppb)(5,5′-mebipy)](PF6)2(complex 4), where 5,5′-mebipy is 5,5′-dimethyl-2,2′-bipyridine and dppb is 1,4-bis(diphenylphosphino)butane, were synthesized and characterized. The structure of complex 2 was determined by X-ray crystallography. These complexes exhibited a higher anti-Trypanosoma cruziactivity than benznidazole, the current antiparasitic drug. Complex 3 was the most potent, displaying a 50% effective concentration (EC50) of 2.1 ± 0.6 μM against trypomastigotes and a 50% inhibitory concentration (IC50) of 1.3 ± 0.2 μM against amastigotes, while it displayed a 50% cytotoxic concentration (CC50) of 51.4 ± 0.2 μM in macrophages. It was observed that the nitrosyl complex 3, but not its analog lacking the nitrosyl group, releases nitric oxide into parasite cells. This release has a diminished effect on the trypanosomal protease cruzain but induces substantial parasite autophagy, which is followed by a series of irreversible morphological impairments to the parasites and finally results in cell death by necrosis. In infected mice, orally administered complex 3 (five times at a dose of 75 μmol/kg of body weight) reduced blood parasitemia and increased the survival rate of the mice. Combination index analysis of complex 3 indicated that itsin vitroactivity against trypomastigotes is synergic with benznidazole. In addition, drug combination enhanced efficacy in infected mice, suggesting that ruthenium-nitrosyl complexes are potential constituents for drug combinations.

scholarly journals Rational synthesis of an atomically precise carboncone under mild conditions

2019 ◽  
Vol 5 (8) ◽  
pp. eaaw0982 ◽  
Author(s):  
Zheng-Zhong Zhu ◽  
Zuo-Chang Chen ◽  
Yang-Rong Yao ◽  
Cun-Hao Cui ◽  
Shu-Hui Li ◽  
...  
Keyword(s):  
Apex Angle ◽  
Facile Synthesis ◽  
Reaction Conditions ◽  
X Ray ◽  
Carbon Allotropes ◽  
X Ray Crystallography ◽  
Mild Conditions ◽  
Research Opportunity ◽  
Insight Into ◽  
Structural Strain

Carboncones, a special family of all-carbon allotropes, are predicted to have unique properties that distinguish them from fullerenes, carbon nanotubes, and graphenes. Owing to the absence of methods to synthesize atomically well-defined carboncones, however, experimental insight into the nature of pure carboncones has been inaccessible. Herein, we describe a facile synthesis of an atomically well-defined carboncone[1,2] (C70H20) and its soluble penta-mesityl derivative. Identified by x-ray crystallography, the carbon skeleton is a carboncone with the largest possible apex angle. Much of the structural strain is overcome in the final step of converting the bowl-shaped precursor into the rigid carboncone under mild reaction conditions. This work provides a research opportunity for investigations of atomically precise single-layered carboncones having even higher cone walls and/or smaller apex angles.

scholarly journals Evolutionary Conservation of Reactions in Translation

2002 ◽  
Vol 66 (3) ◽  
pp. 460-485 ◽  
Author(s):  
M. Clelia Ganoza ◽  
Michael C. Kiel ◽  
Hiroyuki Aoki
Keyword(s):  
Molecular Mechanisms ◽  
Tertiary Structure ◽  
Evolutionary Conservation ◽  
Initiation Factor ◽  
Structural Studies ◽  
X Ray Diffraction ◽  
X Ray ◽  
Common Features ◽  
New Information ◽  
And Function

SUMMARY Current X-ray diffraction and cryoelectron microscopic data of ribosomes of eubacteria have shed considerable light on the molecular mechanisms of translation. Structural studies of the protein factors that activate ribosomes also point to many common features in the primary sequence and tertiary structure of these proteins. The reconstitution of the complex apparatus of translation has also revealed new information important to the mechanisms. Surprisingly, the latter approach has uncovered a number of proteins whose sequence and/or structure and function are conserved in all cells, indicating that the mechanisms are indeed conserved. The possible mechanisms of a new initiation factor and two elongation factors are discussed in this context.

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